Category: Papers
Kinetic network models of tryptophan mutations in β-hairpins reveal the importance of non-native interactions.
We present an analysis of the most extensive explicit-solvent simulations of β-hairpins to date (9.4 ms in aggregate), with the aim of probing the effects of tryptophan mutations on folding. From molecular simulations of GB1 hairpin, trpzip4, trpzip5, and trpzip6 performed on Folding@home, Markov State Models (MSMs) were constructed using a unified set of metastable states, enabling objective comparison of folding mechanisms. MSM models display quantitative agreement with experimental structur…
Read moreSurprisal Metrics for Quantifying Perturbed Conformational Dynamics in Markov State Models.
Markov state models (MSMs), which model conformational dynamics as a network of transitions between metastable states, have been increasingly used to model the thermodynamics and kinetics of biomolecules. In considering perturbations to molecular dynamics induced by sequence mutations, chemical modifications, or changes in external conditions, it is important to assess how transition rates change, independent of changes in metastable state definitions. Here, we present a surprisal metric to qu…
Read moreActivation pathway of Src kinase reveals intermediate states as targets for drug design.
D. Shukla, Y. L. Meng, B. Roux, and V. S. Pande. Nat Commun 5 (2014) Unregulated activation of Src kinases leads to aberrant signalling, uncontrolled growth and differentiation of cancerous…
Read moreStatistical model selection for Markov models of biomolecular dynamics.
R. T. McGibbon, C. R. Schwantes, and V. S. Pande. J Phys Chem B. 118 6475-81 (2014) Markov state models provide a powerful framework for the analysis of biomolecular conformation…
Read moreDynamical Phase Transitions Reveal Amyloid-like States on Protein Folding Landscapes.
J. K. Weber, R. L. Jack, C. R. Schwantes, and V. S. Pande. Biophys J. 107(4) 974-82 (2014). Developing an understanding of protein misfolding processes presents a crucial challenge for…
Read moreDescribing protein folding via temperature-jump two-dimensional infrared spectroscopy and Markov state models.
C. R. Baiz, Y.-S. Lin, C. S. Peng, K. A. Beauchamp, V. A. Voelz, V. S. Pande, and A. Tokmakoff. Biophysical Journal, 106 1359-1370 (2014) The folding mechanism of the…
Read moreCloud-based simulations on Google Exacycle reveal ligand-modulation of GPCR activation pathways.
K. J. Kohlhoff*, D. Shukla*, M. Lawrenz*, G. R. Bowman, D. E. Konerding, D. Belov, R, B. Altman, and V. S. Pande.  Nature Chemistry 6 15-21 (2014) We applied methods developed and honed…
Read moreDynamics of an intrinsically disordered protein reveal metastable conformations that potentially seed aggregation
Amyloid fibril deposits of the intrinsically disordered hIAPP peptide are found in 95% of type II diabetes patients, and the aggregation of this peptide is suggested to induce apoptotic cell-death in insulin-producing β-cells. Understanding the structure and dynamics of the hIAPP monomer in solution is thus important for understanding the nucleation of aggregatio…
Read moreLearning Kinetic Distance Metrics for Markov State Models of Protein Conformational Dynamics.
R. T. McGibbon and V. S. Pande.  J. Chem. Theory Comput., DOI: 10.1021/ct400132h (2013) Building Markov State Models (MSMs) is at the heart of how FAH can take advantage of hundreds of thousands…
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